Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3

EJ Petrie; JJ Sandow; WIL Lehmann; LY Liang; D Coursier; SN Young; WJA Kersten; C Fitzgibbon; AL Samson; AV Jacobsen; KN Lowes; AE Au; H Jousset Sabroux; N Lalaoui; AI Webb; G Lessene; G Manning; IS Lucet; JM Murphy

Journal article

Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3

EJ Petrie, JJ Sandow, WIL Lehmann, LY Liang, D Coursier, SN Young, WJA Kersten, C Fitzgibbon, AL Samson, AV Jacobsen, KN Lowes, AE Au, H Jousset Sabroux, N Lalaoui, AI Webb, G Lessene, G Manning, IS Lucet, JM Murphy

Cell Reports | CELL PRESS | Published : 2019

DOI: 10.1016/j.celrep.2019.08.055

Open access

Abstract

Necroptotic cell death has been implicated in many human pathologies and is thought to have evolved as an innate immunity mechanism. The pathway relies on two key effectors: the kinase receptor-interacting protein kinase 3 (RIPK3) and the terminal effector, the pseudokinase mixed-lineage kinase-domain-like (MLKL). We identify proteins with high sequence similarity to the pseudokinase domain of MLKL in poxvirus genomes. Expression of these proteins from the BeAn 58058 and Cotia poxviruses, but not swinepox, in human and mouse cells blocks cellular MLKL activation and necroptotic cell death. We show that viral MLKL-like proteins function as dominant-negative mimics of host MLKL, which inhibit ..

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University of Melbourne Researchers

Andre Samson Author

Kym Lowes Author

Najoua Lalaoui Author

Andrew Webb Author

Grants

Awarded by Genentech

Funding Acknowledgements

We thank the Walter and Eliza Hall Institute Monoclonal Antibody Facility for their assistance generating the anti-human and anti-mouse RIPK3 antibodies. We are grateful to the National Health and Medical Research Council for fellowship (G.L., 1117089; and J.M.M., 1105754), grant (1124735 and 1124737), and infrastructure (IRIISS 9000433) support and the Victorian Cancer Agency for fellowship support (N.L., 17030), with additional support from the Australian Cancer Research Foundation and the Victorian Government Operational Infrastructure Support scheme. We acknowledge Melbourne Research Scholarship support for L.-Y.L. from the University of Melbourne and support of an Australian Research Training Program Scholarship to A.V.J. We thank Kim Newton and Vishva Dixit for Ripk3<SUP>-/-</SUP> mice, from which MDF cells were derived, and the phospho-mouse RIPK3 antibody; Maria Tanzer for RIPK3<SUP>-/-</SUP> U937 cells; and Toru Okamoto for the pFTRE3G PGK Puro vector.